Congestive heart failure continues to be a leading health concern in Western society. This syndrome is caused by a variety of different diseases with ischemic heart disease being the most common. The prognosis for heart failure patients remains very poor even though some beneficial treatments have recently been developed. The purpose of this research is to identify defective processes that contribute to the initiation and progression of human heart failure in the hope that they can be targeted for improved heart failure therapies The specific aims are to: 1) Determine the in-vivo "contractility reserve" of nonfailing, failing and LVAD-supported human hearts by measuring the changes in cardiac performance caused by increases in heart rate (pacing stress) and adrenergic agonists (dobutamine stress). The most important aspect of these descriptive studies is that we will also obtain tissue samples before and during pacing and during adrenergic stress (and subsequently obtain tissues and myocytes from these hearts when they are explanted) to define the cellular and molecular bases of defective rate and adrenergic responses (Aims 2 and 3). These studies will allow us to translate biochemical, molecular and biophysical abnormalities within single myocytes to impaired function of the intact heart. 2): Determine why SR Ca load does not increase normally (negative versus positive force frequency relationship) when the pacing rate is increased in failing human myocytes (depressed "rate reserve"). The respective roles of the SR (uptake, release and leak), the NCX, the action potential duration and the L-type Ca channel will be studied. 3): Determine why adrenergic agonists do not produce the normal increase in SR Ca loading in failing human myocytes. The respective roles of the SERCA, PLB, RYR and the L-type Ca channel in the inability of adrenergic agonists to increase SR Ca loading and release ("adrenergic reserve") will be studied. These experiments will be performed in nonfailing and failing human hearts to more clearly define the mechanism responsible for abnormal "contractility reserve."